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Trial of PCI-32765 (BTK Inhibitor) in Combination With Carfilzomib in Relapse/Refractory Mantle Cell Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02269085
Recruitment Status : Terminated (slow accrual)
First Posted : October 20, 2014
Last Update Posted : February 28, 2019
Pharmacyclics LLC.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of carfilzomib and ibrutinib that can be given to patients with relapsed or refractory MCL.

Researchers also want to learn if carfilzomib and ibrutinib can help to control the disease.

This is an investigational study. Ibrutinib is FDA approved and commercially available to treat MCL and chronic lymphocytic leukemia (CLL). Carfilzomib is FDA approved and commercially available to treat certain types of multiple myeloma. Giving carfilzomib to patients with MCL is investigational. The combination of ibrutinib and carfilzomib is investigational. The study doctor can explain how the study drugs are designed to work.

Up to 35 participants will be enrolled on this study. All will be enrolled at MD Anderson.

Condition or disease Intervention/treatment Phase
Lymphoma Drug: Ibrutinib Drug: Carfilzomib Behavioral: Phone Calls Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Ibrutinib (BTK Inhibitor) in Combination With Carfilzomib in Relapse/Refractory Mantle Cell Lymphoma
Actual Study Start Date : April 20, 2015
Actual Primary Completion Date : May 29, 2018
Actual Study Completion Date : May 29, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Ibrutinib + Carfilzomib

Phase I: Ibrutinib administered by mouth daily at 420 or 560 mg on Days 1 - 28 of a 28-day cycle. Carfilzomib administered by vein 20/27 mg/m^2, 20/36 mg/m^2, 20/45 mg/m^2 or 20/56 mg/m^2 on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle for Cycles 1- 12 and on Days 1, 2, 15 and 16 for Cycle 13 and higher.

Phase II: Once the MTD has been established 5 additional patients treated at the MTD to a maximum of 35 patients with MCL.

Study staff calls participant after end-of-dosing visit every 6 months for 5 years.

Drug: Ibrutinib

Phase I Starting Dose: 420 mg by mouth daily on Days 1 - 28 of a 28-day cycle.

Phase II Starting Dose: MTD from Phase I.

Other Names:
  • PCI-32765
  • Imbruvica

Drug: Carfilzomib

Phase I Starting Dose: 20 mg/m2 by vein on Days 1, 2, 8 ,9, 15 and 16 in Cycles 1 - 12, and Days 1,2 and 15,16 of Cycle 13 and beyond.

Phase II Starting Dose: MTD from Phase I.

Behavioral: Phone Calls
Study staff calls participant after end-of-dosing visit every 6 months for 5 years. These calls should take about 2-3 minutes.

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Carfilzomib When Given With Ibrutinib [ Time Frame: 28 days ]
    MTD is defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). DLT assessed during the first course of each cohort (28 days), and refers to a study drug related or possibly related event which meets one of the following criteria using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Secondary Outcome Measures :
  1. Response Rate of Carfilzomib When Given With Ibrutinib [ Time Frame: Assessed after two 28 day cycles ]
    Response definitions for measurable disease used from Revised International Workshop Standardized Response Criteria for non-Hodgkin's Lymphoma42. Patients assessed for response after every 2 cycles of therapy. Complete response (CR) defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response (PR) defined as at least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. Stable disease (SD) determined when participant fails to attain criteria needed for a CR or PR, but does not fulfill those for progressive disease. Progressive disease (PD) considered when lymph nodes measure abnormally, if the long axis is more than 1.5 cm regardless of the short axis. If lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more than 1.0.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients must have a confirmed diagnosis of mantle cell lymphoma with positivity in tissue biopsy.
  2. Patients must have previously treated relapsed and/or refractory MCL with at least 2 prior lines of therapy (prior carfilzomib, ibrutinib, bortezomib, anthracycline, rituximab or stem cell transplant are acceptable). There is no upper limit for prior lines of therapy.
  3. Understand and voluntarily sign an institutional review board (IRB)-approved informed consent form.
  4. Age >/= 18 years at the time of signing the informed consent.
  5. Patients must have bi-dimensional measurable disease (Measureable disease by CT scan defined as at least 1 lesion that measures =/>1.5 cm in single dimension.) Patient with leukemia phase (peripheral blood involvement), non-measurable disease, gastrointestinal (GI) MCL, or bone marrow (BM) MCL are also eligible.
  6. Gastrointestinal or bone marrow or spleen only patients are allowable and will be analyzed separately.
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
  8. Serum bilirubin <1.5 mg/dl and creatinine (Cr) Clearance >/= 30 mL/min, platelet count >75,000/mm^3 and absolute neutrophil count (ANC) > 1,500/mm^3, aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 3 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present. (Patients who have bone marrow infiltration by MCL are eligible if their ANC is >/= 1000/mm^3 [growth factor not allowed] or their platelet level is >/= 50,000/mm^3).
  9. Willing and able to participate in all study related procedures and therapy including swallowing capsules without difficulty.
  10. Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test and must be willing to use acceptable methods of birth control during the study and for 30 days after the last dose of study treatment. * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  11. Male patients must use an effective barrier method of contraception during the study and for 30 days following the last dose of study treatment if sexually active with a female of childbearing potential.

Exclusion Criteria:

  1. Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, uncontrolled infection, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form.
  2. Pregnant or breastfeeding females.
  3. Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment.
  4. Prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy. (Patients that require immunosuppressive therapy are not eligible within 60 days of therapy.)
  5. Known human immunodeficiency virus (HIV) infection. Patients with active Hepatitis B infection (not including patients with prior Hepatitis B vaccination; or positive serum Hepatitis B antibody). Hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation.
  6. All patients with central nervous system lymphoma.
  7. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to enrollment.
  8. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
  9. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis.
  10. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib.
  11. Major surgery within 4 weeks of initiation of therapy.
  12. Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
  13. Requires treatment with strong CYP3A inhibitors.
  14. The patient has a prior or concurrent malignancy that in the opinion of the investigator, presents a greater risk to the patient's health and survival, than of the MCL, within the subsequent 6 months at the time of consent. Investigator discretion is allowed.
  15. Patients with New York Heart Association (NYHA) Class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to atrial fibrillation, 2nd degree AV block type II, 3rd degree block, Torsade de pointe, QT prolongation (QTc > 450 msec, sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light headedness and syncope. Patients with atrial fibrillation will be excluded even if they are rate-controlled. If there are any active cardiac issues, cardiology consultation will be obtained for clearance.
  16. Known history of Pulmonary Hypertension
  17. If the left ventricular ejection fraction (LVEF) < 40, patients will be excluded.
  18. Known history of Cardiomyopathy
  19. Acute infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02269085

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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Pharmacyclics LLC.
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Principal Investigator: Hun J. Lee, MD M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT02269085     History of Changes
Other Study ID Numbers: 2013-0677
NCI-2014-02495 ( Registry Identifier: NCI CTRP )
First Posted: October 20, 2014    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by M.D. Anderson Cancer Center:
Mantle cell lymphoma
Relapsed or refractory
Additional relevant MeSH terms:
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Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin